Using the Immune System to Defeat Melanoma

“Go on, tell her,” she urged her husband. “No, you tell her,” he retorted. It was eventually he (whom we’ll call Moshe) who jubilantly shared the news with his doctor. “This morning, I hammered a nail into my living room wall and hung a picture from it!” he excitedly told Dr. Michal Lotem.

Just weeks earlier, Moshe, who is in his early 70s, had been too weak to lift a hammer. He lay motionless in his hospital bed, readying himself for his final goodbyes to his wife, children and grandchildren.

Moshe had come to the Hadassah-Hebrew University Medical Center in Jerusalem more than two years earlier with advanced metastatic melanoma. “We treated him with Zelboraf, a preparation that was new on the market,” says Dr. Lotem, dermatologist, oncologist and head of Hadassah’s Center for Melanoma and Cancer Immunotherapy at the Sharett Institute of Oncology. “At first, he responded well and his disease began to regress.”

Within four months, however, Moshe’s cancer was once more proliferating rapidly. “Conventional treatment had failed,” says Dr. Lotem, “so we put him into an experimental protocol developed at Hadassah. Instead of aiming at his cancer, we targeted his immune system, boosting it to respond more aggressively to the disease.”

Dr. Lotem believes this approach—known broadly as immunotherapy and the focus of much cancer research worldwide—will become the main platform for treating melanoma as well as other types of cancer. “It’s easier on the patient, its side effects vastly more manageable than the hair loss, mouth ulcers, fatigue, vomiting and more caused by chemotherapy and radiation,” she says. “Better yet, not only does the response of patients suggest it may be more effective than anything in the current arsenal, but the quality of their response is far better, too.”

While melanoma is the 19th most common cancer worldwide, its rates are higher in countries with sizeable fair-skinned populations, including Israel, where it is among the 10 most common cancers. Melanoma invades the pigment-producing cells that give skin its color and is aggressive, returning in one in three patients after the first crusty, black skin tumors are cut away. Median survival for metastatic melanoma is six to 12 months.

In a small number of melanoma patients, however, the primary tumor disappears without treatment. This is because the tumor is eradicated by the patient’s immune system, explains Dr. Lotem: “The immune system can defeat cancer, but it rarely enters the fight because cancer creeps under its radar. Malignant cells derive from normal cells. The immune system doesn’t identify them as harmful, leaving them to reproduce and destroy their host.”

Melanoma is what is known as an immunogenic cancer—one in which the immune system plays a major role in its control. It is thus an ideal model for exploring immunotherapy, both for itself and for other cancers.

Finding ways to galvanize the immune system to fight cancer has been an emphasis at the Sharett Institute ever since its director, Dr. Tamar Yablonski Peretz, presciently identified it as a main research goal over 20 years
ago. With her support and encouragement, Dr. Lotem and her team began working on a personalized vaccine to “teach” a patient’s immune systemto recognize the enemy footprint.

“We began by creating traditional vaccines from melanoma cells drawn from patients’ tumors,” Dr. Lotem says. “We irradiated the cells so they couldn’t grow, mixed them with proteins and returned them to the patient in a series of injections.” Administered to some 200 melanoma patients, close to half experienced no recurrence of their illness. “These figures were good, but not good enough,” says Dr. Lotem. “But this one-in-two success rate made it a starting point for other strategies.”

The new strategy switched from a vaccine based on tumor cells that aimed to teach the immune system to recognize the enemy to one made from immune system cells themselves, fortified to fight an enemy they already know. “There are immune system cells in malignant tumors,” says Dr. Lotem. “They’re too scarce to fight off the disease, but they’re not there by chance. They’ve recognized the cancer as wrong.”

Following a two-year fellowship with cancer immunotherapy pioneer Dr. Steven A. Rosenberg at the National Cancer Institute in Bethesda, Md., Dr. Lotem returned to Hadassah in 2004 to create a new-generation personalized melanoma vaccine. “We developed a way of genetically engineering the few thousand immune system cells drawn from a metastasized tumor to number in the trillions,” she explains. At the same time, Lotem’s team is working to boost the immune response of these cells. Last year, investigators in Hadassah’s melanoma center, Drs. Galit Eisenberg and Roni Engelstein, were awarded a three-year, $337,500 grant from the Washington-based Melanoma Research Alliance for developing a protein that will make immune cells better cancer killers.

Propagating the immune system cells drawn from the patient is the responsibility of the department’s chief lab technician, Ina Ben David. Clad in disposable mask, cap, gown and booties, Ben David painstakingly performs the complex chemistry and meticulous safety checks—isolating, purifying, enhancing and multiplying the cells. “The lab holds the cells of only one patient at a time,” she says. “Preparing the cells takes up to 15 days, per individual.”

The patient, meanwhile, is readied by Hadassah’s Department of Bone Marrow Transplantation and Cancer Immunotherapy—Drs. Batia Avni and Sigal Grisaru under department head Dr. Or Reuven—with high-dose chemotherapy, which depletes the patient’s body of existing inefficient immune function. The enhanced anti-melanoma immune cells taken from the patient are then infused in a treatment approved by the United States Food and Drug Administration in 2014.

Moshe is among 16 patients treated, to date, under the Hadassah protocol, which is called Tumor Infiltrating Lymphocytes therapy. “We knew within 24 hours that his treatment was succeeding,” says Dr. Lotem. “The level of cancer markers in his blood was falling fast. We released him from the hospital two weeks later—and four weeks after that, he was hammering nails into his living room wall.”

While the sample of patients is still small and the therapy too recent for the accepted 10-year follow-up needed to be considered a cure, Dr. Lotem and her colleagues have compared their patients with historical controls. They found the immune system to be more active against
the cancer in 75 percent of those treated under the new protocol.
A report of their work in the May 2016 Journal of Immunology Research has attracted substantial positive feedback.

With Hadassah’s Gastrointestinal Cancer Center head, Dr. Ayala Hubert, the melanoma team is planning soon to extend this treatment to patients with colorectal tumors. Ovarian malignancies and those of the lung and breast will then follow.

A patient of Dr. Lotem’s colleague, oncologist Dr. Jonathan Cohen, required the fund’s help. “He’s a man in his 40s, a recent immigrant to Israel who is unmarried and works in a blue-collar job, without family,” says Dr. Cohen. “He has metastatic melanoma. He initially responded to several of the conventional medications, but not for long. His tumors had reached his liver, from where the likelihood of safely getting immune cells is low and the risk of harming the patient while getting them is high—but our radiologists managed to do it. The lab prepared the cells, the bone marrow team jumped our patient to the front of the line—and now we’re waiting to see how he responds to the immune cells we infused.”

Every part of this was expensive, points out Dr. Lotem, “but as long as we had a therapy for him, we weren’t going to say: ‘Sorry, there’s nothing more we can do. Enjoy the time you have left.’ ”

While the researchers dream of an innovative immunotherapy research center, their more immediate concern is how to continue to pay for the existing program once the Adelson fund’s support ends next year. “Despite the huge advances in immune therapy, there’s still a long way to go,” says Dr. Lotem. “There are successes like Moshe, but there are failures, too.”

She, however, has no doubt they are on the right track. “Once you’ve seen you can manipulate the immune system and make it more effective,” Dr. Lotem says, “there’s no way you’re going to give up.”

Wendy Elliman is a British-born science writer who has lived in Israel for more than four decades.

Fighting Melanoma in the United States

This May, Hadassah, the Women’s Zionist Organization of America, has initiated melanoma awareness programs in chapters and units across America (hadassah.org/melanoma). Among the planned events are walkathons, spa days, garden parties and major donor dinners; email health@hadassah.org to be connected to events in your area. The goal of these programs is to educate and empower families to reduce their risks and know the signs of melanoma, and to raise funds for increased melanoma research at Hadassah Medical Organization, like the lifesaving work done by Dr. Michal Lotem.